Cerium oxide nanoparticles (CeONPs) have received much attention because of their excellent catalytic activities, which are derived from quick and expedient mutation of the oxidation state between Ce4+ and Ce3+. The cerium atom has the ability to easily and drastically adjust its electronic configuration to best fit its immediate environment. It also exhibits oxygen vacancies, or defects, in the lattice structure; these arise through loss of oxygen and/or its electrons, alternating between CeO2 and CeO2−x during redox reactions. Being a mature engineered nanoparticle with various industrial applications, CeONP was recently found to have multi-enzyme, including superoxide oxidase, catalase and oxidase, mimetic properties that produce various biological effects, such as being potentially antioxidant towards almost all noxious intracellular reactive oxygen species. CeONP has emerged as a fascinating and lucrative material in biological fields such as bioanalysis, biomedicine, drug delivery, and bioscaffolding. This review provides a comprehensive introduction to CeONP’s catalytic mechanisms, multi-enzyme-like activities, and potential applications in biological fields.